PROJECT SUMMARY Identifying the neurobiological mechanisms that determine response and resistance to psychiatric treatment is of paramount importance for developing improved drugs and therapies. While substantial evidence from humans and rodent models has demonstrated a crucial role for the neurotransmitter, serotonin (5HT), in antidepressant action, it is unknown why some individuals respond to treatment with while others do not. This lack of knowledge limits the development of effective drugs that could specifically target neurobiological substrates that confer treatment response. Our work has revealed that inhibiting the dentate gyrus region of the hippocampus can protect from the development of anxiety-like symptoms in mice, a mechanism that could potentially be used by novel and improved antidepressants. The serotonin 1A receptor (5HT1AR) in dentate gyrus granule neurons is a crucial mediator for neuronal inhibition and behavioral responses to SSRIs. However, how 5HT1ARs regulate neuronal function to elicit an antidepressant response remains elusive. Leading on from these findings, we hypothesize that antidepressant responses are mediated by inhibition of dentate gyrus activity. To test this, we will first examine the complex molecular networks by which 5HT1AR signaling inhibits dentate gyrus activity in mice and in human postmortem brain tissue. Then, we will use chemogenetic techniques to counteract or stimulate neuronal inhibition in the dentate gyrus of transgenic mice that do or do not respond to antidepressants, respectively. Finally, we will use innovative in vivo microscopy to image neuronal activity in the dentate gyrus of freely behaving responders and non-responders during stress and anxiety-related tasks. This project will provide a comprehensive investigation into how we can develop advanced antidepressant treatments based on inhibition of dentate gyrus activity. !